High-frequency haplotypes in the X chromosome locus TLR8 are associated with both CD and UC in females.
BACKGROUND
TNF-alpha and IL-1 have been associated with mucosal inflammation in both Crohn's disease (CD) and ulcerative colitis (UC). Innate immune defects have been associated with CD, specifically CARD15/NOD2. Recently, Toll-like receptor 8 (TLR8) signaling has been shown to enhance generation of both cytokines. Interestingly, TLR8 is located on the X chromosome and inflammatory bowel disease (IBD) has been associated with abnormalities of the X chromosome. The aim was to test whether TLR8 haplotypes are associated with IBD.


METHODS
Subjects (735 CD, 343 UC, 245 controls) were genotyped. Single nucleotide polymorphisms (SNPs) were chosen to tag common Caucasian haplotypes.


RESULTS
Both "risk (H4)" and "protective (H1)" TLR8 haplotypes were observed associated with CD in females. Eighteen percent of CD females had H4 compared with 9% of controls (P = 0.02). Fifty-nine percent of CD females had H1 compared with 72% of controls (P = 0.01). H1 was also negatively associated with UC in females (59% of UC, 72% of controls P = 0.03). Diplotype analysis of CD, UC, and all IBD in females revealed that 2 protective haplotypes (H1/H1) had a markedly diminished odds ratio, 0.4-0.5. The presence of a risk haplotype (H4 / not H1) had a significantly increased odds ratio, 2.0-2.2. Thus, the risk for IBD was 4-5 times higher in females with 1 risk haplotype than with the protective/protective diplotype.


CONCLUSIONS
TLR8 is an X-linked IBD susceptibility gene with both common predisposing and protecting haplotypes. These associations further emphasize the importance of genetic variation in innate immunity as determinants, not only of CD, but of UC as well.
Saruta
Masayuki
M
Inflammatory Bowel Disease Research Center, Cedars-Sinai Medical Center and the UCLA School of Medicine, Los Angeles, California 90048, USA.
Targan
Stephan R
SR
Mei
Ling
L
Ippoliti
Andrew F
AF
Taylor
Kent D
KD
Rotter
Jerome I
JI
D041321:Chromosomes, Human, X / Q000235:genetics*; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D003424:Crohn Disease / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012729:Sex Chromosome Aberrations; D012737:Sex Factors; D051200:Toll-Like Receptor 8 / Q000235:genetics* / Q000378:metabolism
C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; D004247:DNA